Neuromotor development and brain structure in children born extremely preterm

Children born extremely preterm (EPT) are increasingly surviving but it is well known that they face a high risk of brain injury and neurodevelopmental impairments. The overall aim of the studies included in this thesis was to investigate the relationships between brain alterations and neurodevelopment, with specific focus on neuromotor outcomes in children born EPT. The children that took part in these studies were born in Sweden before 27 weeks of gestation, between 1 January 2004 and 31 March 2007. When they reached term equivalent age they underwent a magnetic resonance imaging (MRI) scan of their brain, and this was repeated at 10 years of age. Neurodevelopmental assessments were carried out at 6.5 and 12 years of age. Matched controls also underwent MRI scans at 10 years of age and the 2 developmental assessments at 6.5 and 12 years of age. These were recruited from the Swedish Medical Birth Registry and matched with for postcode, age, maternal country of origin, and sex.

Study I found subtle white matter changes on the MRI brain scans at term age in 59% of the 66 children born EPT who had MRI. There were no significant differences in neurodevelopmental outcomes at 6.5 years of age between the EPT children with and without subtle white matter changes. Study II found that the prevalence of minor neurological dysfunction (MND) was higher in children born EPT than in the term-born control group at 6.5 years of age. MND was associated with motor skills and cognitive abilities. Study III found that children born EPT had significantly smaller regional volumes of the thalamus, the basal ganglia, volumes of structures involved in the brains motor network and the cerebellum than the term-born controls at 10 years of age. EPT-born children with definite motor impairment (≤5 centile) in the subtest of ball skills of the Movement Assessment Battery for Children, Second Edition (MABC-2) at 12 years of age had significantly smaller volumes of the basal ganglia, volumes of structures involved in the brains motor network and the cerebellum than EPT-born children without these problems. Study IV found that the children born EPT with a low-grade intraventricular haemorrhage (IVH) did not have smaller volumes of white or grey matter in the cerebrum or cerebellum at 10 years of age than the EPT children without low-grade IVH. We did not find any differences in motor skills cognitive abilities or visual motor integration between these two groups.

The children born EPT with subtle white matter changes on their MRI scans at term age, or low-grade IVH on their cranial ultrasounds, did not have more neurodevelopmental problems in late childhood than the EPT-born children without these findings. This could possibly be reassuring when discussing such findings with parents of children born EPT. However, children born EPT had worse neurological profiles, with higher prevalence of MND than their term-term peers at 6.5 years of age and these were related to motor skills and cognitive function. The EPT-born children with poorer performance on one of the MABC-2 subtests, ball skills, at 12 years of age had smaller brain volumes than the EPT-born children who did not have these issues. This highlights the importance of follow-up visits and interventions after EPT birth.

List of scientific papers

I. Lina Broström*, Jenny Bolk*, Nelly Padilla, Beatrice Skiöld, Eva Eklöf, Gustaf Mårtensson, Brigitte Vollmer, Ulrika Ådén. Clinical Implications of Diffuse Excessive High Signal Intensity (DEHSI) on Neonatal MRI in School Age Children Born Extremely Preterm. PlosOne. 2016 Feb 17;11(2):e0149578. *These authors contributed equally to this work.
https://doi.org/10.1371/journal.pone.0149578

II. Lina Broström*, Brigitte Vollmer*, Jenny Bolk, Eva Eklöf, Ulrika Ådén. Minor neurological dysfunction and associations with motor function, general cognitive abilities, and behaviour in children born extremely preterm. Developmental Medicine & Child Neurology. 2018 Aug;60(8):826-832. *These authors contributed equally to this work.
https://doi.org/10.1111/dmcn.13738

III. Lina Broström, Hedvig Kvanta, Maria Örtqvist, Nelly Padilla, Ulrika Ådén. Reduced volumes in brain motor areas are related to impaired complex motor skills in children born extremely preterm at late childhood. [Manuscript]

IV. Lina Broström, Lexuri Fernández de Gamarra-Oca, Hedvig Kvanta, Maria Örtqvist, Nelly Padilla, Ulrika Ådén. Low-grade intraventricular haemorrhage, cerebellar growth and neurodevelopment when children born extremely preterm reach late childhood. [Manuscript]